PPM1D (also known as PP2Cδ, Wip1) is a member of the PP2C class of protein phosphates and is known to have a role in regulating cell growth and cellular stress response.
The expression of PPM1D was initially identified as induced in a p53-dependent manner in response to gamma or UV radiation (1), and PPM1D has been implicated in the negative regulation of tumor suppressor pathways (2).
PPM1D mediates feedback regulation of p38-p53 signaling by inactivation of p38 MAP kinase, MAPK/p38 (1, 3-4) via dephosphorylation, which in turn reduces the phosphorylation and activation of p53.
In addition, PPM1D has been shown to dephosphorylate p53 directly (5). Additional functions for PPM1D include the regulation of the base excision pathway of DNA repair (6), progesterone receptor function (7), the homoeostatic regulation of the checkpoint kinases CHK1 and CHK2 (5, 8-11) and the activation of ataxia-telangiectasia mutated (12).
The PPM1D gene maps to 17q23.2, a genomic region recurrently amplified in several types of tumours including medulloblastomas, neuroblastomas, pancreatic adenocarcinomas, ovarian clear cell carcinomas and breast cancer (4, 13-20).
Studies in the Institute of Cancer Research have demonstrated that PPM1D expression and phosphatase activity are required for the survival of cancer cells derived from breast and ovarian clear cell carcinomas harbouring amplification of 17q23.2 (13, 15). All cases harbouring PPM amplification displayed PPM overexpression. PPM amplification was significantly associated with HER2 overexpression, and HER2, TOP2A and CCND1 amplification (16).
These results provide evidence that PPM1D is one of the drivers of this amplicon and that PPM may constitute a therapeutic target for a subgroup of breast and ovarian cancers harbouring PPM1D gene amplification.
The PPM1D gene has been found to be overexpressed and amplified in many types of cancers, including but not limited to breast cancer, gastric carcinomas, ovarian clear cell adenocarcinoma, pancreatic adenocarcinoma, neuroblastomas, and medulloblastomas. Without wishing to be bound by theory, it is thought that PPM1D amplification or overexpression may also be associated with a particularly poor prognosis in these cancers.
PPM has also been identified as a potential therapeutic target in ovarian clear cell carcinomas (15) and breast cancer (23). In addition, it was recently shown that PPM1D confers CDDP (cis-diammine-dichloroplatinum) resistance in OVCA cells, through attenuating CDDP-induced, Chk1-mediated, p53-dependent apoptosis (21).
Tumours with PPM amplification rarely contain p53 mutations and exhibit poorer prognosis than their counterparts with normal PPM1D.
Diagnostic Markers for PPM Amplification
The availability of molecular diagnostics to identify the group of patients that may benefit from PPM1D inhibitors facilitates the development of biology-driven clinical trials to test PPM as a therapeutic target.
The Institute of Cancer Research has developed reagents that can be used for the identification of PPM1D amplification and overexpression in breast cancer archival samples, including a CISH probe for PPM1D (22).
Given the lack of validated anti-PPM1D antibodies that can be applied for immunohistochemistry, a TaqMan based qRT-PCR which has been validated at ICR may constitute an alternative to assess PPM1D expression levels in routinely processed pathological samples, provided that the samples have an excess of 50% of tumour cells.